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Discovery of ‘pliancy genes’ showcases role of latent epigenetic programs in retinal recovery 

Scientists at St. Jude Children’s Research Hospital showed that the open chromatin architecture of Müller glia enables these cells to respond to stress, injury and disease rapidly

Memphis, Tennessee, January 2, 2025

Three women in a lab

First author Jackie Norrie, PhD, with colleagues Danielle Little, PhD, and Marybeth Lupo, PhD, gather near the lattice light sheet microscope to discuss their work.   

The retina is a dynamic tissue of the eye made up of many different types of cells. Scientists at St. Jude Children’s Research Hospital used single-cell sequencing techniques to study retinal cells called Müller glia, showing that these cells have a unique set of “pliancy genes” that are open and accessible to gene expression machinery without being expressed. The work further revealed that these pliancy genes enable Müller glia to summon an inflammatory immune response rapidly under stressful conditions. Understanding how inflammation is triggered in the retina may aid in developing future therapeutics. The work was published today in Developmental Cell.  

Genes contain instructions for how to create proteins, which are used in the body to carry out various functions. DNA-containing genes are housed in chromatin, which can be opened or closed to provide access to these instructions. During development, retinal progenitor cells, the precursors to all the different cell types found in the retina, tightly regulate how chromatin is opened and closed to ensure that the genes needed for cells to function are expressed. As retinal cells differentiate, genes required for rapid growth are turned off and packaged away inside chromatin.  

However, the St. Jude team observed open chromatin regions in Müller glia cells, even though the genes along that open DNA sequence are not expressed. The researchers called these ready but waiting genes pliancy genes as they give Müller glia greater flexibility to enact the latent epigenetic programming that allows them to respond quickly to stress.   

“If a cell is exposed to stress, it may have very little ability to respond if it doesn’t have access to the appropriate genes because of closed chromatin,” explained first author Jackie Norrie, PhD, a scientist in the St. Jude Department of Developmental Neurobiology. “That is why for the retina it is favorable to have a cell type, such as Müller glia, that has these intentional stretches of open chromatin, and thus greater ability to access and turn on the genes needed to quickly respond to stress.”  

Shedding light on genome organization 

For their analysis, the researchers leveraged lattice light sheet (LLS) microscopy.  Compared to other microscopy approaches that use a harsh beam of light, LLS uses a patterned sheet of light, meaning the cells don’t experience the same stresses (phototoxicity) that light beams can cause and can provide more accurate results. The technique also allows researchers to look at the cells from a different angle, providing an even view from all dimensions.  

The researchers found notable differences in how different retinal cell types organize their genome. “Even though all the cells in your body have the same basic map, the same basic genetic instructions, a cell can organize its entire genome very specifically based on its identity and the job that it has to do,” said paper author Marybeth Lupo, PhD, a scientist in the St. Jude Department of Developmental Neurobiology. This allowed the researchers to use the arrangement of DNA in the cells to identify the cell type, setting the stage for work to understand how and why these differences in genome architecture occur.  

Single-cell analysis unlocks Müller glia gene expression patterns  

The researchers coupled their microscopy work with single-cell sequencing. When evaluating retina samples, the dominant cell type in the retina (rods) swamps gene expression signaling and confounds analyses. Single-cell sequencing, such as RNA-seq and ATAC-seq, enables researchers to examine gene expression in specific cell types to better understand how the retina behaves, interacts and responds to stress.  

“Single-cell analysis techniques are transformative in their ability to help us fully understand how distinct populations of cells act during development and under conditions of stress, such as injury or disease,” said corresponding author Michael Dyer, PhD, St. Jude Department of Developmental Neurobiology chair. “We’ve done a lot of work looking at cellular tissue heterogeneity, and it’s clear that leveraging these techniques allows us to understand the programming that drives the response of distinct cell populations, which can be blurred in bulk samples.” 

 
 

Müller glia perform various essential functions in the retina, helping to maintain retinal homeostasis. To understand what the pliancy genes observed in Müller glia do, the researchers subjected their retinal cell samples to different forms of stress. 

Understanding Müller glia’s role in inflammatory response  

The researchers subjected their retinal samples to 15 different simulated stress conditions mimicking illness or injury, such as heating or cooling the samples to replicate fever or hypothermia conditions, adding glucose to replicate diabetic retinopathy or introducing yeast to trigger retinitis. Additionally, the researchers replicated conditions linked to eye infections (a leading cause of blindness worldwide) and excitotoxicity, among others.  

The transcriptional analysis needed to interpret the data was possible through collaboration with computational scientists. “Bringing together computational approaches with the bench work from the laboratory enables us to take an integrated approach,” said co-author Danielle Little, PhD, a postdoctoral fellow in the Dyer Lab. “By using three different computational tools, we were able to identify different groups of genes associated with each other and co-segregate across the data set. 

“This is how we were able to identify transcription factors that are key regulators of a cell’s stress response,” she added. 

Many genes expressed in response to the various stresses were involved in inflammation, a standard reaction to disease or injury. When the retina is stressed, Müller glia can rapidly express their pliancy genes’ signaling through cytokines to mount an inflammatory immune response. Inflammation contributes to many retinal diseases, making this new understanding of how inflammation is triggered important for developing future treatment approaches.  

“By leveraging single-cell analysis techniques, we showed that the unique open chromatin of Müller glia gives them the ability to rapidly respond to stress,” said Norrie. “This permissive environment for quick cytokine expression to recruit inflammatory factors and spark an immune response is driving the way the retina responds to illness and injury.”   

Authors and funding 

The study’s other authors include Abbas Shirinifard, Akhilesh Mishra, Qiong Zhang, Natalie Geiger, Daniel Putnam, Nadhir Djekidel, Cody Ramirez, Beisi Xu, Jacob Dundee, Jiyang Yu and Xiang Chen, all of St. Jude.  

The study was supported by the National Institutes of Health (CA225442, CA245508, EY030180, and CA21765) and ALSAC, the fundraising and awareness organization of St. Jude.  

 
 

St. Jude Children's Research Hospital

St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer, sickle cell disease, and other life-threatening disorders. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 60 years ago. St. Jude shares the breakthroughs it makes to help doctors and researchers at local hospitals and cancer centers around the world improve the quality of treatment and care for even more children. To learn more, visit stjude.org, read St. Jude Progress, a digital magazine, and follow St. Jude on social media at @stjuderesearch.

 
 
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